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OBJECTIVEThe aim of this study was to describe cross-sectional and longitudinal associations between glycated hemoglobin (HbA1c) levels and strategies to control type 2 diabetes with baseline levels and 8-year changes in a deficit accumulation frailty index (FI), a commonly used marker of biological aging.RESEARCH DESIGN AND METHODSWe conducted exploratory analyses from 4,169 participants, aged 45–76 years, who were followed in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, pooling data across intervention groups. We related baseline and 8-year levels of HbA1c with FI scores using analyses of variance and covariance. Associations between 8-year changes in FI and the use of diabetes medication classes and weight changes were assessed with control for HbA1c levels. Inverse probability weighting was used to assess bias associated with differential follow-up.RESULTSBaseline and average HbA1c levels over time of 5% were independently associated with slower increases in frailty.CONCLUSIONSLower HbA1c levels among individuals with diabetes are associated with slower biological aging as captured by a deficit accumulation FI. Strategies to control diabetes through weight loss or metformin use may also slow aging.

Biologic aging reflects the genetic, molecular, and cellular changes underlying the development of morbidity and mortality with advancing chronological age. As several potential mechanisms have been identified, there is a growing interest in developing robust measures of biologic age that can better reflect the underlying biology of aging and predict age-related outcomes. To support this endeavor, the Research Centers Collaborative Network (RCCN) conducted a workshop in January 2022 to discuss emerging concepts in the field and identify opportunities to move the science forward. This paper presents workshop proceedings and summarizes the identified research needs, priorities, and recommendations for measuring biologic age. The highest priorities identified were the need for more robust measures, longitudinal studies, multidisciplinary collaborations, and translational approaches.

Background Substantive previous work has shown that both gait speed and global cognition decline as people age. Rates of their decline, as opposed to cross-sectional measurements, could be more informative of future functional status and other clinical outcomes because they more accurately represent deteriorating systems. Additionally, understanding the sex and racial disparity in the speed of deterioration, if any, is also important as ethnic minorities are at an increased risk of mobility disability and dementia. Method Data from 2 large longitudinal intervention studies were integrated. Rates of decline were derived from individual-level measures of gait speed of 400-m walk and scores on the Modified Mini Mental State Examination (3MSE). We also assessed age-associated declines and accelerations in changes across the ages represented in the studies (age range 53–90). Results The mean rate of decline in 400-m gait speed across individuals was 0.03 m/s per year, and multivariable analysis showed a significant acceleration in decline of −0.0013 m/s/y2 (p < .001). Both race and sex moderated the rate of decline. For global cognition, the mean rate of decline was 0.05 of a point per year on the 3MSE scale, and acceleration in the rate of decline was significant (−0.017 point/y2, p < .001), but neither sex nor race moderated the decline. Conclusion Rate of decline in physical but not cognitive function appears moderated by sex and race. This finding, as well as rates and accelerations of decline estimated herein, could inform future intervention studies. Clinical Trials Registration Number NCT00017953 (Look AHEAD); NCT01410097 (Look AHEAD ancillary); NCT00116194 (LIFE).

BackgroundRisk factors for cognitive decline and physical decline have been studied independently, however older adults might experience decline in both areas i.e., dual decline. Risk factors associated with dual decline are largely unknown and have significant implications on health outcomes. The aim of this study is to explore risk factors associated with dual decline.MethodsUsing data from the Health, Aging and Body Composition (Health ABC) study, a longitudinal prospective cohort study, we examined trajectories of decline based on repeated measures of the Modified Mini-Mental State Exam (3MSE) and the Short Physical Performance Battery (SPPB) across 6 years (n=1,552). We calculated four mutually exclusive trajectories of decline and explored predictors of decline: cognitive decline (n = 306) = lowest quartile of slope on the 3MSE or 1.5 SD below mean at baseline, physical decline (n = 231) = lowest quartile of slope on the SPPB or 1.5 SD below mean at baseline, dual decline (n = 110) = lowest quartile in both measures or 1.5 SD below mean in both measures at baseline. Individuals who did not meet criteria for one of the decline groups were classified as the reference group. (n= 905).ResultsMultinomial logistic regression tested the association of 17 baseline risk factors with decline. Odds of dual decline where significantly higher for individuals at baseline with depressive symptoms (CES-D >16) (Odds Ratio (OR)=2.49, 95% Confidence Interval (CI): 1.05-6.29), ApoE-ε4 carrier (OR= 2.09, 95% CI: 1.06-1.95), or if individuals had lost 5+lbs in past year (OR=1.79, 95% CI: 1.13-2.84). Odds were significantly lower for individuals with a higher score on the Digit Symbol Substitution Test per standard deviation (OR per SD: 0.47, 95% CI 0.36-0.62) and faster 400-meter gait (OR per SD= 0.49, 95% CI: 0.37-0.64).ConclusionAmong predictors, depressive symptoms at baseline significantly increased the odds of developing dual decline but was not associated with decline in the exclusively cognitive or physical decline groups. APOE-ε4 status increased the odds for cognitive decline and dual decline but not physical decline. More research on dual decline is needed because this group represents a high risk, vulnerable subset of older adults.

Background To evaluate whether contrast sensitivity is associated with lower extremity physical function in cognitively intact older adults. Methods Cross-sectional analysis of the relationship of binocular and worse eye log contrast sensitivity (LCS) to expanded Short Physical Performance Battery (eSPPB) and its components (gait speed, narrow walking speed, chair stand pace, and balance) in 192 cognitively healthy older adults. The association of LCS with postural sway and gait was also tested with tasks that further challenged functional reserve. Results Mean age was 76.4 years with 56% identifying as female and over 98.5% having good corrected visual acuity. Lower LCS was significantly associated with worse performance on the eSPPB, 4-M gait speed, narrow walking speed, and balance time in unadjusted and adjusted models. The relationship between worse eye LCS and larger postural sway was 3 times greater on a foam surface (beta 1.07, 95% CI [0.35, 1.80]) than a firm surface (beta 0.35, 95% CI [0.05, 0.65]), and both were robust to adjustment for confounders; similar findings were observed with binocular LCS. Lower binocular LCS had a greater decremental effect on gait velocity during the fast pace (beta −0.58, 95% CI [−0.90, −0.27]) than the usual pace (Beta −0.39 [−0.63, −0.15]) gait task. Conclusions These findings suggest that cognitively unimpaired older adults without significant visual acuity impairment can have subtle preclinical deficits in contrast sensitivity and physical function that could place them at risk of mobility and balance issues. Future studies should determine whether this subset of older adults may benefit from targeted intervention to prevent disability.

Background and objectivesAlthough evidence exists that measures of mobility and cognition are correlated, it is not known to what extent they overlap, especially across various domains. This study aimed to investigate the intersection of 18 different objective cognitive and physical function measures from a sample of unimpaired adults aged 70 years and older.Research design and methodsCanonical correlation analysis was utilized to explore the joint cross-sectional relationship between 13 cognitive and 6 physical function measures in the baseline visit of the Brain Networks and Mobility Function (B-NET) Study (n = 192).ResultsMean age of participants was 76.4 years. Two synthetic functions were identified. Function 1 explained 26.3% of the shared variability between the cognition and physical function variables, whereas Function 2 explained 19.5%. Function 1 termed “cognitive and physical speed” related the expanded Short Physical Performance Battery (eSPPB), 400-m walk speed, and Dual Task gait speed measures of physical function to semantic fluency animals scores, Digit Symbol Coding (DSC), and Trail Making Test B. Function 2 termed “complex motor tasks and cognitive tasks” related the Force Plate Postural Sway Foam Task and Dual Task to the following cognitive variables: MoCA Adjusted Score, Verbal Fluency L words, Craft story immediate and delayed recall, and Trail Making Test B.Discussion and implicationsWe identified groups of cognitive and physical functional abilities that were linked in cross-sectional analyses, which may suggest shared underlying neural network pathway(s) related to speed (Function 1) or complexity (Function 2).Translational significanceWhether such neural processes decline before measurable functional losses or may be important targets for future interventions that aim to prevent disability also remains to be determined.

Cellular metabolism generates molecular damage affecting all levels of biological organization. Accumulation of this damage over time is thought to play a central role in the aging process, but damage manifests in diverse molecular forms complicating its assessment. Insufficient attention has been paid to date to the role of molecular damage in aging-related phenotypes, particularly in humans, in part because of the difficulty in measuring its various forms. Recently, omics approaches have been developed that begin to address this challenge, because they are able to assess a sizeable proportion of age-related damage at the level of small molecules, proteins, RNA, DNA, organelles and cells. This review describes the concept of molecular damage in aging and discusses its diverse aspects from theoretical models to experimental approaches. Measurement of multiple types of damage enables studies of the role of damage in human aging outcomes and lays a foundation for testing interventions to reduce the burden of molecular damage, opening new approaches to slowing aging and reducing its consequences.

BackgroundCardiorespiratory fitness and perceived fatigability are interrelated components of physical capacity that may jointly influence movement within one’s living environment (life-space mobility). We examined whether fitness and fatigability were associated with life-space mobility in community-dwelling older adults, and whether the association of fitness with life-space varied by the level of perceived fatigability.MethodsParticipants were from the Study of Muscle, Mobility and Aging (SOMMA) baseline cohort (N = 775, mean age 76.1 years). Life Space Assessment scores incorporated level, frequency, and assistance used (personal, devices) for life-space mobility. Fitness was measured as VO2peak from symptom-limited treadmill testing. Fatigability cut-points included: (i) Borg Rating of Perceived Exertion (RPE) ≥ 10 after a fixed-speed (1.5 mph) treadmill test, (ii) the Pittsburgh Fatigability Scale (PFS) Physical ≥ 15, and (iii) PFS Mental ≥ 13. The total count of cut-points was used as a composite fatigability measure (range: 0–3). Linear regressions were adjusted for demographic, lifestyle, and health confounders.ResultsBetter fitness was associated with greater life-space, but the association plateaued at higher fitness levels (VO2peak > 18). Life-space was significantly lower for individuals meeting ≥2 fatigability criteria (vs none), attributable mainly to more severe physical, but not mental, fatigability. In moderation analyses, the fitness–life-space association was significant only for those with RPE ≥ 10 but did not differ by PFS.ConclusionFitness below a critically low threshold was associated with limited life-space mobility, suggesting that certain older individuals may need to operate close to their maximum aerobic capacity to traverse daily environments; these associations were driven by those with more severe physical fatigability.

OBJECTIVE: The aim of this study was to describe cross-sectional and longitudinal associations between glycated hemoglobin (HbA1c) levels and strategies to control type 2 diabetes with baseline levels and 8-year changes in a deficit accumulation frailty index (FI), a commonly used marker of biological aging. RESEARCH DESIGN AND METHODS: We conducted exploratory analyses from 4,169 participants, ages 45-76, who were followed in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, pooling data across intervention groups. We related baseline and 8-year levels of HbA1c with FI scores using analyses of variance and covariance. Associations between 8-year changes in FI and the use of diabetes medication classes and weight changes were assessed with control for HbA1c levels. Inverse probability weighting was used to assess bias associated with differential follow-up. RESULTS: Baseline and average HbA1c levels over time of >8%, were associated with less increase in FI scores over 8 years (both p<0.002). After adjustment for HbA1c, use of metformin and weight loss >5% were independently associated with slower increases in frailty. CONCLUSIONS: Lower HbA1c levels among individuals with diabetes are associated with slower biological aging as captured by a deficit accumulation FI. Strategies to control diabetes through weight loss or metformin use may also slow aging.

BackgroundMitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness, is largely understudied.MethodsIn the Study of Muscle, Mobility, and Aging, we collected vastus lateralis biopsies from older adults (n = 879, 70–94 years, 59.2% women). Maximal State 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta coefficients expressed per 1-SD increment in the independent variable.ResultsMax OXPHOS was associated with leg power for both women (β = 0.12 Watts/kg, p < .001) and men (β = 0.11 Watts/kg, p < .050). ATPmax was associated with leg power for men (β = 0.09 Watts/kg, p < .05) but was not significant for women (β = 0.03 Watts/kg, p = .11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, β women = 1.03 mL/kg/min, β men = 1.32 mL/kg/min; ATPmax β women = 0.87 mL/kg/min, β men = 1.50 mL/kg/min; all p < .001).ConclusionsHigher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power.

Treatments that target fundamental processes of aging are expected to delay several aging-related conditions simultaneously. Testing the efficacy of these treatments for potential anti-aging benefits will require clinical trials with endpoints that reflect the potential benefits of slowing processes of aging. There are several potential types of endpoints to capture the benefits of slowing a process of aging, and a consensus is needed to standardize and compare the results of these trials and to guide the analysis of observational data to support trial planning. Using biomarkers instead of clinical outcomes would substantially reduce the size and the duration of clinical trials. This requires validation of surrogate markers showing that treatment induced change in the marker reliably predicts the magnitude of change in the clinical outcome. The surrogate marker must also reflect the biological mechanism for the effect of treatment on the clinical outcome. “Biological age” is a superficially attractive marker for such trials. However, it is essential to establish that treatment induced change in biological age reliably predict the magnitude of benefits in the clinical outcome. Reaching consensus on clinical outcomes for geroscience trials and then validating potential surrogate biomarkers requires time, effort, and coordination that will be worthwhile to develop surrogate outcomes that can be trusted to efficiently test the value of many anti-aging treatments under development.

BackgroundTo assess the relationship between self-reported and performance-based visual impairment (VI) and lower extremity physical function.MethodsCross-sectional analysis of 2 219 Health ABC participants who completed vision testing and the Short Physical Performance Battery (SPPB). Linear regression models used either self-reported (weighted visual function question [VFQ] score) or performance-based (visual acuity [VA], log contrast sensitivity [LCS], Frisby stereoacuity [SA]) to predict SPPB or its components—gait speed, chair stands, or standing balance—with and without covariate adjustment.ResultsMean age was 73.5 years (range 69–80); 52.4% were female and 37.4% African American. All VI measures were strongly associated with SPPB in unadjusted and adjusted models (p < .001). A self-reported VFQ score 1 standard deviation lower than the mean (mean 87.8 out of 100) demonstrated a −0.241 (95% confidence interval [CI]: −0.325, −0.156) adjusted difference in SPPB. After controlling for covariates, VA of 85 arcsec (30%) had a −0.449 (−0.627, −0.271) adjusted SPPB score versus those with better visual function. LCS < 1.55 (28.6%) was associated with a −0.759 (−0.938, −0.579) lower and LCS ≤ 1.30 (8%) with a −1.216 (−1.515, −0.918) lower adjusted SPPB score relative to better LCS. In a final multivariable model containing multiple vision measures, LCS remained independently associated with SPPB and all components, while SA remained associated with balance (all p < .05).ConclusionsBoth self-reported and performance-based VI are strongly associated with poor lower extremity physical function. These findings may identify a subgroup of older adults with co-existing visual and physical dysfunction who may benefit from targeted screening and intervention to prevent disability.

Among older women, the clinical presentation of urinary incontinence (UI) is heterogeneous; presenting as a pelvic floor condition or geriatric syndrome. We aimed to characterize the geriatric incontinence syndrome (GIS) to establish its foundation in clinical practice.Prospective study.Geriatric Clinical Research Unit.Sixty-one community-dwelling women aged 70 and older with bothersome UI symptoms.UI symptom type and severity were determined by 3-day bladder diary. UI severity was defined; moderate UI defined as2 UI episodes/day and severe UI defined as ≥2 UI episodes/day. Subjective assessment of physical performance was determined using the Short Physical Performance Battery (SPPB) score. Total SPPB scores9 define normal physical performance and scores ≤9 defined impaired physical performance.The average age was 77.1 ± 5.8 (mean ± SD) years; 69% of women had severe UI and 31% had moderate UI. Demographic characteristics were similar between groups. Daytime voiding frequency was 7.1 ± 2.9 and nocturia was present equally between groups. The majority of women (59%) with severe UI had SPPB ≤9 compared with 26% among women with moderate UI (p = 0.02); featuring significantly slower chair stand scores (2.3 ± 1.4 vs 3.3 ± 0.9, p = 0.007) and gait speed (0.08 ± 0.2 m/s compared with 1.0 ± 0.2 in women with moderate UI).A multifactorial GIS may be present in older women evidenced by the co-existence of severe UI, physical disability, slower chair stand pace, and gait speed. Prospective studies are needed to understand how these clinical features may impact the clinical care of older incontinent women.

Biologic aging reflects the genetic, molecular, and cellular changes underlying the development of morbidity and mortality with advancing chronological age. As several potential mechanisms have been identified, there is a growing interest in developing robust measures of biologic age that can better reflect the underlying biology of aging and predict age-related outcomes. To support this endeavor, the Research Centers Collaborative Network (RCCN) conducted a workshop in January 2022 to discuss emerging concepts in the field and identify opportunities to move the science forward. This paper presents workshop proceedings and summarizes the identified research needs, priorities, and recommendations for measuring biologic age. The highest priorities identified were the need for more robust measures, longitudinal studies, multidisciplinary collaborations, and translational approaches.

Aging affects men and women differently; however, the impact of sex and gender on the aging process is not well understood. Moreover, these 2 concepts are often conflated, which further contributes to a lack of clarity on this important issue. In an effort to better understand the relevance of sex and gender in aging research, the Research Centers Collaborative Network sponsored a 1.5-day conference on sex and gender differences in aging that brought together key thought leaders from the 6 National Institute on Aging center programs. The meeting included sessions on comparing males and females, pathophysiological differences, sex/gender in clinical care, and gender and health in the social context. Presenters from a wide array of disciplines identified opportunities for multidisciplinary research to address current gaps in the field and highlighted the need for a more systematic approach to understanding the how and why of sex/gender differences, as well as the health implications of these differences and the sex/gender biases that affect clinical treatment and outcomes. This article summarizes the proceedings of the workshop and provides several recommendations to move the field forward, such as better data collection tools to assess the intersection of sex and gender in epidemiological research; a life course perspective with attention to fetal/developmental origins and key life stages; innovative animal models to distinguish contributions from sex hormones versus sex chromosomes; and integration of sex/gender into teaching and clinical practice. Ultimately, successful implementation of these recommendations will require thoughtful investigations across the translational spectrum and increased collaborations among those with expertise in sex and gender differences.

Modifying unhealthy behaviors and/or environments may improve or maintain an older adult’s health. However, achieving and sustaining behavior change is challenging and depends upon clinical, social, psychological, and political domains. In an effort to highlight the multidisciplinary nature of behavior change, the National Institute on Ageing (NIA) Research Centers Collaborative Network (RCCN) held a two-day workshop, achieving and sustaining behavior change for older adults. The workshop was informed by the socioecological model and designed to initiate dialogue around the individual, community, and systems-level determinants of behavior change. This article summarizes key topics presented during the workshop, discusses opportunities for future research, education, and training, and recommends how each of the six NIA research centers may pursue work in behavior change for older adults.

BACKGROUND: Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20–30 ng/mL) for skeletal health. OBJECTIVES: We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults’ physical function. METHODS: Using 5 large prospective, population-based studies—Age, Gene/Environment Susceptibility-Reykjavik (n = 4858, Iceland); Health, Aging, and Body Composition (n = 2494, United States); Invecchiare in Chianti (n = 873, Italy); Osteoporotic Fractures in Men (n = 2301, United States); and Study of Osteoporotic Fractures (n = 5862, United States)—we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged ≥65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women

Higher dietary protein, alone or in combination with physical activity (PA), may slow the loss of age-related muscle strength in older adults. We investigated the longitudinal relationship between protein intake and grip strength, and the interaction between protein intake and PA, using four longitudinal ageing cohorts. Individual participant data from 5584 older adults (52 % women; median: 75 years, IQR: 71·6, 79·0) followed for up to 8·5 years (mean: 4·9 years, SD: 2·3) from the Health ABC, NuAge, LASA and Newcastle 85+ cohorts were pooled. Baseline protein intake was assessed with food frequency questionnaires and 24-h recalls and categorized into < 0·8, 0·8–SD (95 % CI: –0·026, –0·006) every year. No associations were found between protein intake, measured at baseline, and grip strength, measured prospectively, or rate of decline of grip strength in models adjusted for sociodemographic, anthropometric, lifestyle and health variables (e.g., protein intake ≥ 1·2 v· < 0·8 g/kg aBW/d: β = –0·003, 95 % CI: –0·014, 0·005 SD per year). There also was no evidence of an interaction between protein intake and PA. We failed to find evidence in this study to support the hypothesis that higher protein intake, alone or in combination with higher PA, slowed the rate of grip strength decline in older adults.

Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer’s disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

Immune cells drive chronic inflammation underlying obesity-related T2DM. We previously reported a cholesterol metabolism pathway as the top coordinated transcriptional module in human monocytes associated with both obesity and T2DM (FDR In conclusion, weight loss induces beneficial changes in the cholesterol metabolism pathway in monocytes, a potential therapeutic target for obesity-related T2DM. Disclosure J.Ding: Research Support; Medifast, Inc. K.Lohman: None. S.B.Kritchevsky: None. J.S.Parks: None. I.Hoeschele: None. B.J.Nicklas: None. J.Demons: None. Y.Liu: None. Funding National Institutes of Health (R01DK103531)

BACKGROUNDPhysical resilience with age is considered a key feature of healthy aging, but current understanding of the neural contributions to resilience is limited. Additionally, few methods exist to identify physical resilience and observe the mechanisms through which resilience manifests.METHODSTo address these gaps, we used data from 189 participants from the Brain Networks and Mobility (B-NET) study who completed the short physical performance battery (SPPB) as well as its expanded version (eSPPB), magnetic resonance imaging (MRI), and functional MRI (fMRI). Functional brain networks were generated using graph theory methods. We grouped participants based on SPPB scores (RESULTSHigher SPPB scores were associated (pCONCLUSIONSIncreased connectivity between SMN and ACC may be a marker of physical resilience within the brain.

To examine associations between frailty and drug, alcohol, and tobacco use among a large diverse cohort of people with HIV (PWH) in clinical care in the current era.PWH at 7 sites across the United States completed clinical assessments of patient-reported measures and outcomes between 2016 and 2019 as part of routine care including drug and alcohol use, smoking, and other domains. Frailty was assessed using 4 of the 5 components of the Fried frailty phenotype and PWH were categorized as not frail, pre-frail, or frail. Associations of substance use with frailty were assessed with multivariate Poisson regression.Among 9336 PWH, 43% were not frail, 44% were prefrail, and 13% were frail. Frailty was more prevalent among women, older PWH, and those reporting current use of drugs or cigarettes. Current methamphetamine use (1.26: 95% CI 1.07-1.48), current (1.65: 95% CI 1.39-1.97) and former (1.21:95% CI 1.06-1.36) illicit opioid use, and former cocaine/crack use (1.17: 95% CI 1.01-1.35) were associated with greater risk of being frail in adjusted analyses. Current smoking was associated with a 61% higher risk of being frail vs. not frail (1.61: 95% CI 1.41-1.85) in adjusted analyses.We found a high prevalence of prefrailty and frailty among a nationally distributed cohort of PWH in care. This study identified distinct risk factors that may be associated with frailty among PWH, many of which, such as cigarette smoking and drug use, are potentially modifiable.

BACKGROUND: Protein intake recommendations advise ≥0.8 g/kg body weight (BW)/d, whereas experts propose a higher intake for older adults (1.0-1.2 g/kg BW/d). It is unknown whether optimal protein intake differs by sex or race.OBJECTIVES: We examined the shape of sex- and race-specific associations of dietary protein intake with 3- and 6-y changes in appendicular lean mass (aLM) and gait speed and also 6-y incidence of mobility limitation in community-dwelling older men and women.METHODS: We used data on men (n = 1163) and women (n = 1237) aged 70-81 y of the Health, Aging, and Body Composition Study. Protein intake was assessed using an FFQ (1998-1999). aLM and gait speed were measured at baseline and at 3 and 6 y. Difficulty walking one-quarter mile or climbing stairs was measured every 6 mo over 6 y. Prospective associations were evaluated with linear and Cox regression models, comparing fit of models with and without spline functions. All analyses were stratified by sex and additionally by race.RESULTS: Mean ± SD protein intake was 0.94 ± 0.36 g/kg adjusted body weight (aBW)/d in men and 0.95 ± 0.36 g/kg aBW/d in women. There were no strong indications of nonlinear associations. In women, higher protein intake was associated with less aLM loss over 3 y (adjusted B per 0.1 g/kg aBW/d: 39.4; 95% CI: 11.6, 67.2), specifically in black women, but not over 6 y or with gait speed decline. In men, protein intake was not associated with changes in aLM and gait speed. Higher protein intake was associated with a lower risk of mobility limitation in men (adjusted HR per 1.0 g/kg aBW/d: 0.55; 95% CI: 0.34, 0.91) and women (adjusted HR: 0.56; 95% CI: 0.33, 0.94), specifically white women.CONCLUSIONS: Associations between protein intake and physical outcomes may vary by sex and race. Therefore, it is important to consider sex and race in future studies regarding protein needs in older adults.

Background Individuals are often counseled to use behavioral weight loss strategies to reduce risk for cardiovascular disease (CVD). We examined whether any benefits for CVD risk from weight loss intervention extend uniformly to individuals across a range of underlying health states. Methods The time until first occurrence of a composite of fatal and nonfatal myocardial infarction and stroke, hospitalized angina, or CVD death was analyzed from 8 to 11 years of follow-up of 4,859 adults who were overweight or obese, aged 45–76 years with Type 2 diabetes. Individuals had been randomly assigned to either an intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Participants were grouped by intervention assignment and a frailty index (FI) based on deficit accumulation, ordered from fewer (first tertile) to more (third tertile) deficits. Results Baseline FI scores were unrelated to intervention-induced weight losses and increased physical activity. The relative effectiveness of ILI on CVD incidence was inversely related to baseline FI in a graded fashion (p = .01), with relative benefit (hazard ratio = 0.73 [95% CI 0.55,0.98]) for individuals in the first FI tertile to no benefit (hazard ratio = 1.15 [0.94,1.42]) among those in the third FI tertile. This graded relationship was not seen for individuals ordered by age tertile (p = .52), and was stronger among participants aged 45–59 years (three-way interaction p = .04). Conclusions In overweight/obese adults with diabetes, multidomain lifestyle interventions may be most effective in reducing CVD if administered before individuals have accrued many age-related health deficits. However, these exploratory analyses require confirmation by other studies. Clinical Trial Registration NCT00017953

Introduction Mild parkinsonian signs (MPS) are associated with morbidity. Identification of MPS progression markers may be vital for preventive management, yet has not been pursued. This study aimed to ascertain clinical/neuroimaging features predictive of MPS progression. Methods 205 participants in the Health ABC Study were included. MPS was defined using published guidelines. MPS progression was evaluated by determining UPDRS-III change between baseline and follow-up ≥2 years later. Standard brain MRI and DTI were obtained at baseline. Correlation coefficients between demographics, vascular risk factors, imaging markers, and UPDRS-III change were adjusted for follow-up time. Linear regression was used to adjust for possible confounders in the relationship between imaging markers and MPS progression. Results 30% of participants had baseline MPS. Demographics and risk factors did not differ significantly between participants with MPS (MPS+) and without MPS (MPS-). Mean follow-up time was 3.8±0.8 years. Older age, male gender, diabetes were associated with faster rate of UPDRS-III change in MPS- but not MPS+ participants. Among MPS- participants, the only imaging marker associated with faster UPDRS-III progression was higher gray matter mean diffusivity (MD), widespread in various cortico-subcortical bihemispheric regions, independent of age, gender, diabetes. No imaging features were associated with UPDRS-III change among MPS+ participants. Conclusions Lower gray matter integrity predicted MPS progression in those who did not have baseline MPS. Microstructural imaging may capture early changes related to MPS development, prior to macrostructural change. Any future management promoting gray matter preservation may inhibit MPS development.

OBJECTIVES: To investigate changes in inflammatory biomarkers during induction therapy for older adults with acute myeloid leukemia (AML) and their associations with geriatric assessment (GA) measures and outcomes. METHODS: This was a single institution ancillary study to a prospective observational study (N=20 consecutive adults aged ≥60 with newly diagnosed AML who received induction chemotherapy). Biomarkers (Interleukin-6 [IL-6], IL-6 soluble receptor [IL-6 sR], tumor necrosis factor alpha [TNFα], TNFα soluble receptor 1 [TNFα sR1], interleukin- 3 [IL-3], C-reactive protein [CRP]) were collected at start of induction, weekly for three weeks, and post-induction and were compared over time using paired t-tests. GA was administered at baseline and post-induction, and correlated with biomarker levels using Spearman correlations. Survival was estimated using Kaplan-Meier and compared by categorized biomarker level using Wilcoxon tests. RESULTS: Biomarker levels were stable during induction, except for CRP and IL-6 sR. Declines in objectively measured physical function [Short Physical Performance Battery (SPPB); r=0.71, p

Mitigating age-related disease and disability presents challenges. Physical activity (PA) may be influential for prolonging health and functioning, warranting characterization of its patterns over the life course in population-based data. With the availability of up to three self-reported assessments of past year leisure-time PA (LTPA) over multiple decades in 15,036 participants (26% African American; 55% women; mean baseline age=54; median follow-up=23 years) from the Atherosclerosis Risk in Communities (ARIC) Study sampled from four U.S. communities, race-sex-stratified trajectories of average weekly intensity (metabolic equivalent of task (MET)), duration (hours), and energy expenditure or volume (MET-h) of LTPA were developed from age 45 to 90 using joint models to accommodate expected non-ignorable attrition. Declines in weekly LTPA intensity, duration, and volume from age 70 to 90 were observed in white women (2.9 to 1.2 MET; 2.5 to 0.6 h; 11.1 to 2.6 MET-h), white men (2.5 to 1.0 MET; 3.5 to 1.8 h; 15.5 to 6.4 MET-h), African American women (2.5 to 2.4 MET; 0.8 to 0.1 h; 6.7 to 6.0 MET-h), and African American men (2.3 to 1.4 MET; 1.5 to 0.6 h; 8.0 to 2.3 MET-h). These data reveal population-wide shifts towards less active lifestyles in older adulthood.

The difference in the estimated glomerular filtration rate based on cystatin C and that based on creatinine (eGFRDiff) is known to be associated with frailty and mortality. Creatinine is influenced by muscle mass, more so than cystatin C; we aimed to determine whether eGFRDiff is associated with muscle quantity and to what extent muscle quantity explains the relationship between eGFRDiff and poor functional status.A cohort analysis of the health, aging, and body composition study (HABC).Overall, 2,970 HABC participants had their baseline serum creatinine level, cystatin C level, and body composition measured using imaging.Estimated glomerular filtration rates (eGFRs) were calculated using Chronic Kidney Disease Epidemiology Collaboration equations (estimated glomerular filtration rate based on cystatin C [eGFRThe total thigh muscle area was evaluated using computed tomography. The health, aging, and body composition study physical performance battery was scored on a continuous scale (standing and walking tasks); poor functional status was characterized by the lowest quartile.We used linear regression to model the cross-sectional association of eGFRDiff and muscle measures. We used logistic regression to evaluate the association of eGFRDiff with poor functional status.The mean age was 74 ± 3 years; the eGFRThe functional status outcome was specific to HABC. The muscle measures did not capture dynamic turnover.The difference of eGFR

Background. Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE) (control) in 5145 individuals with overweight/obesity and type 2 diabetes, found no significant differences in all-cause or cardiovascular mortality or morbidity during 9.6 (median) years of intervention. Participants in ILI who lost ≥10% at 1 year had lower risk of composite cardiovascular outcomes relative to DSE. Objective: Since effects of ILI may take many years to emerge, we conducted intent-to-treat analyses comparing mortality in ILI over 16.7 years (9.6 year of intervention and then observation) to DSE. In a secondary exploratory analysis, we compared mortality by magnitude of weight loss in ILI relative to DSE. Methods. Primary outcome was all-cause mortality from randomization to 16.7 years. Other outcomes included cause-specific mortality, interactions by sub-groups (age, sex, race/ethnicity, CVD history) and an exploratory analysis by magnitude of weight loss in ILI vs DSE as reference. Analyses used proportional hazards regression and likelihood ratio. Results. The incidence of all-cause mortality did not differ significantly in ILI and DSE (549 and 589 participants respectively); HR = 0.91; 95% CI (0.81,1.02), p=0.11. There were no significant differences between treatments in cause-specific mortality or within prespecified subgroups. ILI participants who lost ≥10% at 1 year had a 21% reduced risk of mortality (HR=0.79, CI 0.67,0.94, p=0.007) relative to DSE. Conclusions. ILI focused on weight loss did not significantly affect mortality risk. However, ILI participants who lost ≥10% had reduced mortality relative to DSE.

To examine the role of physical function impairments on the change in urinary incontinence (UI) symptoms after pelvic floor muscle training in older women.This is a prospective cohort study of 70 community-dwelling participants, older than age 70 years, with at least moderate incontinence symptoms. A comprehensive pelvic floor and physical function assessment was done at baseline. Individualized pelvic floor muscle training prescriptions with behavioral management strategies to reduce incontinence episodes were provided for 12 weeks. Baseline physical function was determined using the SPPB (Short Physical Performance Battery). A total score of 9 or lower out of 12 indicated impaired physical function, and scores higher than 9 indicated normal physical function. A 3-day bladder diary established daily incontinence episodes. The between-group difference in the change in number of UI episodes, from baseline to 6 weeks, was our primary outcome. Descriptive analyses compared important demographic and clinical characteristics. Longitudinal mixed model linear regression analyses determined the change in incontinence episodes and estimates of improvement based on the presence of impaired physical function and adjusted for age, race, and body mass index (BMI).Participants' mean±SD age was 76.9±5.4 years, and 15.7% identified as African American, with no significant differences in age or race between groups. Participants with impaired physical function had higher mean±SD BMI (33.6±14.5 vs 27.4±5.8; P=.03) and more baseline incontinence episodes (4.5±2.9 vs 2.7±2.1 episodes per day; P=.005) than in women without functional impairment. After 6 weeks of pelvic floor exercises, the change in number of incontinence episodes per day was not different between participants with physical functional impairment compared with women with normal physical function (mean [95% CI] -1.2 [-2.0 to -0.5] vs -0.4 [-1.1 to 0.3], P=.31). Overall, after 12 weeks of pelvic floor muscle training, complete satisfaction with incontinence symptom improvement was low for both groups (41.8% with physical function impairments vs 44.8% with normal physical function; P=.90).Behavioral therapy including pelvic floor muscle training may not significantly decrease UI symptoms to a degree that is satisfactory in women who are older than 70 years and are seeking treatment for UI, regardless of the presence of physical function impairments.ClinicalTrials.gov, NCT03057834.

ObjectiveTo examine the role of physical function impairments on the change in urinary incontinence symptoms after pelvic floor muscle training in older women.MethodsThis is a prospective cohort study of 70 community-dwelling women, older than 70 years, with at least moderate incontinence symptoms. A comprehensive assessment of pelvic floor and physical function was done at baseline. Individualized PFM training prescriptions with behavioral management strategies to reduce incontinence episodes were provided for 12 weeks. Baseline physical function was determined using the Short Physical Performance Battery (total score of ≤9/12 defined impairment). A 3-day bladder diary established daily incontinence episodes. The change in urinary incontinence episodes based on presence of physical function impairment was our primary outcome. Descriptive analyses compared important demographic and clinical characteristics. Longitudinal mixed model linear regression analyses were used to assess for change in incontinence and estimate of improvement based on the presence of physical function impairment adjusted for age, race, and BMI.ResultsParticipants’ mean±SD age was 76.9±5.4 years and 15.7% were African American with no significant differences in age or race between groups. Women with physical function impairment had higher mean ± SD BMI (33.6±14.5 vs 27.4±5.8 kg/m2; p=0.03) and significantly greater baseline incontinence episodes (4.5±2.9 vs. 2.7±2.1 episodes/day; p=0.005) than in women without functional impairment, respectively. After 6 weeks of pelvic floor exercises, women with physical functional impairment had a non-significant decrease in incontinence episodes/day compared to women with normal physical function (mean [95%CI], −1.2 [−2.0,−0.5] vs −0.4 [−1.1, 0.3], p=0.31). Women with physical function impairments also reported lower improvement in their incontinence symptoms compared to women without functional impairment (50.7±5.9% vs 64.2±5.9%, p=0.08).ConclusionsNon-surgical therapy to include pelvic floor muscle training may not significantly decrease urinary incontinence symptoms to a degree that is satisfactory in women older than 70 years seeking treatment for urinary incontinence.

Older adults are often underrepresented in clinical research, even though older adults are major consumers of novel therapies. We present major themes and recommendations from the 2021 "Inclusion of Older Adults in Clinical Research" Workshop, convened by the Clinical and Translational Science Award (CTSA) Inclusion of Older Adults as a Model for Special Populations Workgroup and the Research Centers Collaborative Network (RCCN). The goal of this workshop was to develop strategies to assist the research community in increasing the inclusion of older adults in clinical research. Major identified barriers include historical lack of federal guidelines, ageist biases and stereotypes, and lack of recruitment and retention techniques or infrastructure focused on older adults. Three key recommendations emerged: 1) engaging with the policymaking process to further promote inclusion; 2) using the CTSA Workgroup Presentation Materials Library and other resources to overcome ageism, and 3) building institutional capacity to support age inclusion.

Background and objectives Hypertension is associated with significant morbidity and mortality despite effective antihypertensive therapies. Soluble klotho is a circulating protein that in preclinical studies is protective against the development of hypertension. There are limited studies of klotho and blood pressure in humans. Design, setting, participants, & measurements Within the Health, Aging, and Body Composition Study, a cohort of well-functioning older adults, soluble klotho was measured in serum. We evaluated the cross-sectional and longitudinal association between klotho and blood pressure, prevalent hypertension, incident hypertension, and BP trajectories. Analyses were adjusted for demographics, cardiovascular disease and kidney disease risk factors, and measures of mineral metabolism including calcium, phosphate, parathyroid hormone, 25(OH) vitamin D, and fibroblast growth factor 23. Results The median klotho concentration was 630 pg/ml (478–816, 25th to 75th percentile). Within the cohort, 2093 (76%) of 2774 participants had prevalent hypertension and 476 (70%) of the remaining 681 developed incident hypertension. There was no association between klotho and prevalent hypertension or baseline systolic BP, but higher klotho was associated with higher baseline diastolic BP (fully adjusted β=0.92 mmHg, 95% confidence interval, 0.24 to 1.60 mmHg, higher per two-fold higher klotho). Higher baseline serum klotho levels were significantly associated with a lower rate of incident hypertension (fully adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.93 for every two-fold higher klotho). Higher klotho was also associated with lower subsequent systolic BP and diastolic BP (−0.16, 95% confidence interval, −0.31 to −0.01, mmHg lower systolic BP per year and −0.10, 95% confidence interval, −0.18 to −0.02, mmHg lower diastolic BP per year, for each two-fold higher klotho). Conclusions Higher klotho is associated with higher baseline diastolic but not systolic BP, a lower risk of incident hypertension, and lower BP trajectories during follow-up.

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Intermediate endpoints are needed to evaluate the effect of interventions targeting the biology of aging in clinical trials. A working group identified five blood-based biomarkers that may serve such a purpose as an integrated index. We evaluated the responsiveness of the panel to caloric restriction or aerobic exercise in the context of a randomized clinical trial conducted in patients with heart failure with preserved ejection fraction (HFpEF) with obese phenotype who were predominantly female. Obese HFpEF is highly prevalent in women, and is a geriatric syndrome whose disease pathology is driven by non-cardiac factors and shared drivers of aging. We measured serum Interleukin-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-b-type natriuretic peptide at baseline and after 20 weeks in older participants with stable obese HFpEF participating in a randomized, controlled, 2 × 2 factorial trial of caloric restriction and/or aerobic exercise. We calculated a composite biomarker index, summing baseline quintile scores for each biomarker, and analyzed the effect of the interventions on the index and individual biomarkers and their associations with changes in physical performance. This post hoc analysis included 88 randomized participants (71 women [81%]). The mean ± SD age was 66.6 ± 5.3 years, and body mass index (BMI) was 39.3 ± 6.3 kg/m(2). Using mixed models, mean values of the biomarker index improved over 20 weeks with caloric restriction (− 0.82 [Formula: see text] 0.58 points, p = 0.05), but not with exercise (− 0.28 [Formula: see text] 0.59 points, p = [Formula: see text] ), with no evidence of an interaction effect of CR [Formula: see text] EX [Formula: see text] time (p = 0.80) with adjustment for age, gender, and BMI. At baseline, the biomarker index was inversely correlated with 6-min walk distance, scores on the short physical performance battery, treadmill test peak workload and exercise time to exhaustion (all [Formula: see text] (s) = between − 0.21 and − 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed ([Formula: see text] (s) = − 0.31). Among older patients with chronic obese HFpEF, caloric restriction improved a biomarker index designed to reflect biological aging. Moreover, the index was associated with physical performance and exercise tolerance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00509-9.

Background Cut-points to define slow walking speed have largely been derived from expert opinion. Methods Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4–6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not. Results Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as “fast”; 478 (9.5%) as “intermediate” (walking speed ≥0.62 m/s but Conclusions Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

Clinical trials conventionally test aggregate mean differences and assume homogeneous variances across treatment groups. However, significant response heterogeneity may exist. The purpose of this study was to model treatment response variability using gait speed change among older adults participating in caloric restriction (CR) trials. Eight randomized controlled trials (RCTs) with five- or six-month assessments were pooled, including 749 participants randomized to CR and 594 participants randomized to non-CR (NoCR). Statistical models compared means and variances by CR assignment and exercise assignment or select subgroups, testing for treatment differences and interactions for mean changes and standard deviations. Continuous equivalents of dichotomized variables were also fit. Models used a Bayesian framework, and posterior estimates were presented as means and 95% Bayesian credible intervals (BCI). At baseline, participants were 67.7 (SD = 5.4) years, 69.8% female, and 79.2% white, with a BMI of 33.9 (4.4) kg/m2. CR participants reduced body mass [CR: -7.7 (5.8) kg vs. NoCR: -0.9 (3.5) kg] and increased gait speed [CR: +0.10 (0.16) m/s vs. NoCR: +0.07 (0.15) m/s] more than NoCR participants. There were no treatment differences in gait speed change standard deviations [CR–NoCR: -0.002 m/s (95% BCI: -0.013, 0.009)]. Significant mean interactions between CR and exercise assignment [0.037 m/s (95% BCI: 0.004, 0.070)], BMI [0.034 m/s (95% BCI: 0.003, 0.066)], and IL-6 [0.041 m/s (95% BCI: 0.009, 0.073)] were observed, while variance interactions were observed between CR and exercise assignment [-0.458 m/s (95% BCI: -0.783, -0.138)], age [-0.557 m/s (95% BCI: -0.900, -0.221)], and gait speed [-0.530 m/s (95% BCI: -1.018, -0.062)] subgroups. Caloric restriction plus exercise yielded the greatest gait speed benefit among older adults with obesity. High BMI and IL-6 subgroups also improved gait speed in response to CR. Results provide a novel statistical framework for identifying treatment heterogeneity in RCTs.

Recent studies have suggested that 25-hydroxyvitamin D (25(OH)D) may be a poor biomarker of bone health, in part because measured levels incorporate both protein-bound and free vitamin D. The ratio of its catabolic product (24,25-dihydroxyvitamin D [24,25(OH)2 D]) to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide more information on sufficient vitamin D stores and is not influenced by vitamin D-binding protein concentrations. We evaluated whether the VMR or 25(OH)D are more strongly associated with bone loss and fracture risk in older adults. We performed a retrospective cohort study of 786 community-dwelling adults aged 70 to 79 years who participated in the Health Aging and Body Composition study. Our primary outcomes were annual changes in bone density and incident fracture. The mean age of these participants was 75 ± 3 years, 49% were female, 42% were Black, and 23% had an estimated glomerular filtration rate (eGFR)

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

Increased inflammation associated with leaky gut is a major risk factor for morbidity and mortality in older adults; however, successful preventive and therapeutic strategies against these conditions are not available. In this study, we demonstrate that a human-origin Lactobacillus paracasei D3-5 strain (D3-5), even in the non-viable form, extends life span of Caenorhabditis elegans. In addition, feeding of heat-killed D3-5 to old mice (> 79 weeks) prevents high- fat diet-induced metabolic dysfunctions, decreases leaky gut and inflammation, and improves physical and cognitive functions. D3-5 feeding significantly increases mucin production, and proportionately, the abundance of mucin-degrading bacteria Akkermansia muciniphila also increases. Mechanistically, we show that the lipoteichoic acid (LTA), a cell wall component of D3-5, enhances mucin (Muc2) expression by modulating TLR-2/p38-MAPK/NF-kB pathway, which in turn reduces age-related leaky gut and inflammation. The findings indicate that the D3-5 and its LTA can prevent/treat age-related leaky gut and inflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-019-00137-4) contains supplementary material, which is available to authorized users.

PURPOSE: To examine whether long-term fish oil (FO) supplementation is associated with a lower risk of mobility disability and enhances benefits of physical activity. METHODS: 1635 sedentary adults aged 70 to 89 years from the Lifestyle Interventions and Independence for Elders (LIFE) single-blinded randomized, multi-center clinical trial, which compared a structured physical activity (PA) program to a health education (HE) program. Primary outcome was incident major mobility disability (MMD), defined by loss of ability to walk 400m, measured every 6 months for an average of 2.6 years. Secondary outcomes included persistent mobility disability (PMD), Short Physical Performance Battery (SPPB), 400m walk speed, and grip strength. RESULTS: A third of participants reported using FO at baseline (456, 28%; mean age, 78.5 years; 70.5% women). MMD was experienced by 131 participants (28.7%) in the FO group and 405 (34.4%) participants in the nonuser group. After adjusting for confounders, FO supplementation was associated with a lower risk (hazard ratio [HR], 0.78; 95% CI, 0.64–0.96) of incident MMD. However, there was no interaction (P= .19) between FO supplementation and PA intervention for MMD. For the secondary outcome of PMD, the intervention association differed by supplementation (P= .002) with PA intervention associations of (HR, 1.36; 95% CI, 0.83–2.23) for users and (HR, 0.61; 95% CI, 0.46–0.81) for nonusers. Changes in physical performance outcomes were not modified by baseline FO supplementation or combination with PA. CONCLUSIONS: FO supplementation was associated with a lower risk of major mobility disability in low to moderate functioning older adults. However, supplementation did not enhance the benefit of physical activity on risk of mobility disability. These results are hypothesis generating and need to be confirmed in randomized trials.